Myocardial infarction and hypertrophic cardiomyopathy followed by heart failure is a major cause of death worldwide. As the terminally differentiated adult cardiomyocytes (CMs) possess a very limited innate ability to regenerate, much research has focused on exploring the potential of mesenchymal stem cells (MSC) and induced pluripotent stem cells (iPSC) to repair the damaged myocardium. However with regards to benefits till date, experimental and clinical trials have shown sub-optimal to modest results. The main drawback for this is that the mechanisms involved for the in vivo therapy is not well understood. Suggested pathways include permanent or partial cell fusion between stem cells and resident cardiac cells, transdifferentiation of stem cells into cardiac and vascular cells and secretion of pro-angiogenic paracrine factors. However, none of them have considered the fact that the continuously beating cardiac microenvironment can also induce significant mechanobiological effects on the transplanted stem cells that can influence their overall fate and functionality. In this project we aim to study, for the first time, the fundamental mechanobiological interactions between stem cells (iPSC and MSC) and contractile cardiomyocytes (under normal and diseased conditions) in a continuously beating 3D cardiac tissue environment. In pursuit of this research goal, we will develop a microscale device using human iPSC-derived beating CMs to assay the combined effects of mechanical, biochemical and architectural factors on mechanobiology of transplanted stem cells and their therapeutic potential in cardiomyopathy. We expect this novel miniaturized biomimetic cardiac tissue model will help decipher the specific roles of individual biomechanical forces imposed by the spontaneously beating cardiac microenvironment on the transplanted stem cells. The study will also help identify the role of rhythmic mechanical environments, ECM stiffness, focal adhesion signal molecules and their cross-talks to regulate MSC mechanotranduction, paracrine signaling, epigenetic profile, differentiation abilities and cell fate. As a broader impact, this study will provide better understanding of stem cell fate in vivo, enabling highly safe and efficacious cell-based myocardial therapy.